Zubsolv

SIDE EFFECTS

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

Clinical Trials Experience

The safety of buprenorphine/naloxone was evaluated in 497
opioid-dependent subjects. The prospective evaluation of buprenorphine/naloxone
was supported by clinical trials using buprenorphine tablets without naloxone
and other trials using buprenorphine sublingual solutions. In total, safety
data were available from 3214 opioid-dependent subjects exposed to
buprenorphine at doses in the range used in treatment of opioid addiction.

Table 1: Adverse Events > 5% by Body System and
Treatment Group in a 4-week Study

Body System / Adverse Event (COSTART Terminology)

N (%)

N (%)

Buprenorphine/ naloxone 16mg/day
N=107

Placebo
N=107

Body as a Whole

Asthenia

7 (6.5%)

7 (6.5%)

Chills

8 (7.5%)

8 (7.5%)

Headache

39 (36.4%)

24 (22.4%)

Infection

6 (5.6%)

7 (6.5%)

Pain

24 (22.4%)

20 (18.7%)

Pain Abdomen

12 (11.2%)

7 (6.5%)

Pain Back

4 (3.7%)

12 (11.2%)

Withdrawal Syndrome

27 (25.2%)

40 (37.4%)

Cardiovascular System

Vasodilation

10 (9.3%)

7 (6.5%)

Digestive System

Constipation

13 (12.1%)

3 (2.8%)

Diarrhea

4 (3.7%)

16 (15.0%)

Nausea

16 (15.0%)

12 (11.2%)

Vomiting

8 (7.5%)

5 (4.7%)

Nervous System

Insomnia

15 (14.0%)

17 (15.9%)

Respiratory System

Rhinitis

5 (4.7%)

14 (13.1%)

Skin And Appendages

Sweating

15 (14.0%)

11 (10.3%)

The adverse event profile of
buprenorphine was also characterized in the dose-controlled study of
buprenorphine solution, over a range of doses in four months of treatment.
Table 2 shows adverse events reported by at least 5% of subjects in any dose
group in the dose-controlled study.

Table 2: Adverse Events ( ≥ 5%) by Body System
and Treatment Group i n a 16-week Study

Post-marketing Experience

The following adverse
reactions have been identified during post-approval use of buprenorphine and
naloxone sublingual tablets. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably
estimate a causal relationship to drug exposure.

The most frequently reported
post-marketing adverse event not observed in clinical trials was peripheral
edema.

DRUG INTERACTIONS

Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers

Buprenorphine is metabolized to norbuprenorphine
primarily by cytochrome CYP3A4; therefore, potential interactions may occur
when ZUBSOLV sublingual tablets is given concurrently with agents that affect
CYP3A4 activity. The concomitant use of ZUBSOLV sublingual tablet with CYP3A4
inhibitors (e.g., azole antifungals such as ketoconazole, macrolide antibiotics
such as erythromycin, and HIV protease inhibitors) should be monitored and may
require dose-reduction of one or both agents.

The interaction of buprenorphine with CYP3A4 inducers has
not been studied; therefore, it is recommended that patients receiving ZUBSOLV
sublingual tablets be monitored for signs and symptoms of opioid withdrawal if
inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin,
rifampicin) are co-administered [see CLINICAL PHARMACOLOGY]

Antiretrovirals

Three classes of antiretroviral agents have been
evaluated for CYP3A4 interactions with buprenorphine. Nucleoside reverse
transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450
enzyme pathway, thus no interactions with buprenorphine are expected.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized
principally by CYP3A4. Efavirenz, nevirapine and etravirine are known CYP3A
inducers whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic
interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine
have been shown in clinical studies, but these pharmacokinetic interactions did
not result in any significant pharmacodynamic effects. It is recommended that
patients who are on chronic buprenorphine treatment have their dose monitored
if NNRTIs are added to their treatment regimen. Studies have shown some
antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity
(nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on
buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other
PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir)
resulted in elevated levels of buprenorphine and norbuprenorphine and patients
in one study reported increased sedation. Symptoms of opioid excess have been
found in post-marketing reports of patients receiving buprenorphine and
atazanavir with and without ritonavir concomitantly. Monitoring of patients
taking buprenorphine and atazanavir with and without ritonavir is recommended,
and dose reduction of buprenorphine may be warranted.

Benzodiazepines

There have been a number of
post-marketing reports regarding coma and death associated with the concomitant
use of buprenorphine and benzodiazepines. In many, but not all of these cases,
buprenorphine was misused by self-injection. Preclinical studies have shown
that the combination of benzodiazepines and buprenorphine altered the usual
ceiling effect on buprenorphine-induced respiratory depression, making the
respiratory effects of buprenorphine appear similar to those of full opioid
agonists. ZUBSOLV sublingual tablets should be prescribed with caution to
patients taking benzodiazepines or other drugs that act on the CNS, regardless
of whether these drugs are taken on the advice of a physician or are being
abused/misused. Patients should be warned that it is extremely dangerous to
self-administer non-prescribed benzodiazepines while taking ZUBSOLV sublingual
tablets, and should also be cautioned to use benzodiazepines concurrently with
ZUBSOLV sublingual tablets only as directed by their physician.

Drug Abuse And Dependence

Controlled Substance

Buprenorphine is a Schedule III narcotic under the
Controlled Substances Act.

Under the Drug Addiction Treatment Act (DATA) codified
at 21 U.S.C. 823(g), prescription use of this product in the treatment of
opioid dependence is limited to physicians who meet certain qualifying
requirements, and who have notified the Secretary of Health and Human Services
(HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique
identification number that must be included on every prescription.

Abuse

Buprenorphine, like morphine
and other opioids, has the potential for being abused and is subject to
criminal diversion. This should be considered when prescribing or dispensing
buprenorphine in situations when the clinician is concerned about an increased
risk of misuse, abuse, or diversion. Healthcare professionals should contact
their state professional licensing board or state controlled substances
authority for information on how to prevent and detect abuse or diversion of
this product.

Patients who continue to
misuse, abuse, or divert buprenorphine products or other opioids should be
provided with, or referred to, more intensive and structured treatment.

Abuse of buprenorphine poses a
risk of overdose and death. This risk is increased with the abuse of
buprenorphine and alcohol and other substances, especially benzodiazepines.

The physician may be able to
more easily detect misuse or diversion by maintaining records of medication
prescribed including date, dose, quantity, frequency of refills, and renewal
requests of medication prescribed.

Proper assessment of the
patient, proper prescribing practices, periodic re-evaluation of therapy, and
proper handling and storage of the medication are appropriate measures that
help to limit abuse of opioid drugs.

Dependence

Buprenorphine is a partial
agonist at the mu-opioid receptor and chronic administration produces physical
dependence of the opioid type, characterized by moderate withdrawal signs and
symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is
typically milder than seen with full agonists and may be delayed in onset [seeWARNINGS
AND PRECAUTIONS]

A neonatal withdrawal syndrome
has been reported in the infants of women treated with buprenorphine during
pregnancy. [seeWARNINGS AND PRECAUTIONS]

Last reviewed on RxList: 7/18/2013
This monograph has been modified to include the generic and brand name in many instances.